NARRATIVE Project 6 entitled Multimodal Longitudinal Network Bioimaging? will combine task-free fMRI, longitudinal structural MRI and molecular imaging with the novel tau PET tracer [18F]AV1451 to determine how progressive regional brain atrophy and tau deposition in FTD relate to the healthy functional connectome. The overarching goal is to extend and refine a network-based neurodegeneration model developed in the previous cycle to predict regional progression of neurodegeneration and molecular pathology in patients with FTD. Converging data from in vitro experiments and animal models suggest that pathological tau spreads trans-synaptically across inter-connected networks, driving disease progression. We have previously shown that cross-sectional FTD-related atrophy patterns reflect the connectional architecture of the healthy brain, consistent with trans- neuronal spread of toxic misfolded proteins. However, the ability of the ?network-based neurodegeneration model? to predict longitudinal disease progression remains to be tested. In this project we will approach this question by using the healthy brain functional connectome to model longitudinal changes in structural MRI and [18F]AV1451 binding in patients with FTD syndromes strongly associated with underlying tau pathology: bvFTD due to MAPT mutations, PSP-S and CBS. Patients will be recruited through Core A (Clinical), genotyped through Core D (Genetics) and imaged through Core E (Imaging). Our connectivity models will incorporate node-level graph metrics that we have previously developed (shortest path to an epicenter) as well as a novel ?nodal hazard? score that incorporates a node's connectional proximity to its nearest network neighbors and the baseline involvement (atrophy or tau) of those neighbors. We will determine whether patient-tailored epicenters, reflecting each patient's anatomical profile, improve model fit and single-subject prediction of progression. Finally, we will begin to explore the temporal relationship between spread of tau and neurodegeneration. Our overarching hypothesis is that tau aggregation begins in vulnerable syndrome- and patient-specific epicenters and spreads trans-synaptically into neighboring nodes, which, in turn, disseminate tau along connections, driving neurodegeneration. To test this model, we will pursue the following specific aims: (1) To determine how the healthy brain functional connectome relates to FTD-related baseline AV1451 binding and longitudinal progression of AV1451 binding and atrophy, (2) To optimize methods for predicting longitudinal FTD-related AV1451 binding and atrophy progression in individual patients, (3) To compare the distribution of FTD-related AV1451 binding and brain atrophy at baseline and at 12 months follow-up. If successful, this project will provide initial in vivo evidence directly linking the spread of tau to brain connectivity and downstream neurodegeneration, advancing our understanding of disease mechanisms, and informing the development of tau-based therapies.